Long-term potentiation and depression (LTP and LTD) are promising and widely studied examples of vertebrate synaptic plasticity. In LTP and LTD there is a persistent synaptic enhancement or decrement, respectively, seen following brief conditioning periods of synaptic activity. In both these forms of plasticity, which are leading models of memory, the trafficking of AMPA receptors (-Rs) at synapses plays a key role. The general aim of this grant has been to examine the subcellular signaling controlling AMPA-R trafficking. Recently, we have found that beta amyloid (A?), a peptide strongly implicated as a causative agent in Alzheimer's disease, has pronounced effects on AMPA-R trafficking. In this grant period, we will examine how A? can control the trafficking of synaptic AMPA receptors. Our recent studies show that A? recruits signaling used in LTD to remove synaptic AMPA receptors. Furthermore, loss of synaptic AMPA receptors leads to loss of dendritic spines and NMDA receptors; that is, loss of the synapse. Here we will determine the mechanisms by which A? leads to these events. Several complementing methodologies will be used, including molecular biology, electrophysiology, two-photon laser scanning microscopy, and electron microscopy. These studies will use organotypic rat hippocampal slices, dissociated cultured neurons and transgenic mice. The results of these studies will elucidate the mechanisms underlying Alzheimer's disease as well as provide potentially efficacious treatment strategies. The specific aims are to determine: SA1: If A? allosterically up-modulates NMDA-R function; SA2: How A? interacts with synaptic plasticity; SA3: How A? leads to removal of synaptic AMPA-Rs; SA4: How A? leads to loss of synapses. There is growing evidence that one of the first targets of dysfunction in Alzheimer's disease is the synapse. We will examine the mechanisms by which beta amyloid, a molecule strongly implicated in the etiology of the disease, leads to synaptic dysfunction. By elucidating these mechanisms we will identify potentially therapeutic targets in the treatment of Alzheimer's disease.